Cardiac pacing system by substituting native biological regulatory function

ABSTRACT

The present invention provides a cardiac pacing system based on biological activities, comprising: a) at least one nerve activity sensing means which senses nerve activity of a cardiac sympathetic nerve and/or a vagal nerve, and outputs a plurality of input nerve activity signals; b) a calculating means which receives the input nerve activity signals, calculates a transfer function by computing a Fourier transform of normal nerve activity signals and a normal heart rate signal from normal cardiovascular system, calculates an impulse response by computing an inverse Fourier transform of the transfer function, calculates a plurality of pacing signals for control of a heart rate using a convolution integral between the input nerve activity signals and the impulse response, and outputs the pacing signals; and c) a pacing means which receives the pacing signals, and stimulates the heart based on the pacing signals such that heart rate is regulated.

REFERENCE TO RELATED APPLICATIONS

This is a divisional patent application of copending application Ser.No. 12/103,786, filed Apr. 16, 2008, entitled “CARDIAC PACING SYSTEM,BLOOD PRESSURE REGULATING SYSTEM, AND CARDIAC DISEASE TREATMENT SYSTEMBY SUBSTITUTING NATIVE BIOLOGICAL REGULATORY FUNCTION”, which is adivisional application of application Ser. No. 10/523,539, filed Feb. 3,2005, entitled “MEDICAL TREATMENT SYSTEM BY SUBSTITUTING NATIVEBIOLOGICAL REGULATORY FUNCTION; CARDIAC PACING SYSTEM, BLOOD PRESSUREREGULATING SYSTEM, AND CARDIAC DISEASE TREATMENT SYSTEM BASED ON THEMEDICAL TREATMENT SYSTEM”, now U.S. Pat. No. 7,835,791, issued Nov. 16,2010. The aforementioned applications are hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is related to a cardiac pacing system, a bloodpressure regulating system, and a cardiac disease treatment system bysubstituting native biological regulatory function. More particularly,the present invention provides a cardiac pacing system, a blood pressureregulating system, and a cardiac disease treatment system bysubstituting native biological regulatory function that is capable ofregulating organs as if their central controllers were normallyfunctioning even if the central controllers themselves become abnormaldue to various causes.

2. Description of Related Art

Heart transplantation from brain dead subjects became legal in Japan totreat patients with severe heart failure. However, the number of heartdonors is definitely small, and the shortage of hearts fortransplantation has been seriously discussed worldwide.

An alternative treatment for patients with severe heart failure isartificial heart implantation. However, even the most recent artificialhearts are not regulated by native biological regulation, thereby theydo not always operate in concert with native organs.

Pacemakers have been used for the treatment of patients withbradycardia. Pacemakers enable necessary rhythmic myocardial contractionby electrically stimulating the myocardium artificially.

Recently rate-responsive pacemakers have been developed, in whichstimulation rate changes according to the estimated native heart ratefrom e.g., electrocardiographic QT time, body temperature, or bodyacceleration. However, specificity, sensitivity and transient responseof heart rate regulation compared to native heart rate regulation bysuch pacemakers have not always been satisfactory.

In some other diseases, it is well known that abnormal native regulatoryfunction promotes disease processes. For example, it is known thatabnormal native regulatory mechanisms participate in the progression ofheart disease, and it is well known that sympathetic nerveoveractivation and abnormal vagal nerve withdrawal occur after the onsetof acute myocardial infarction, and worsens the outcome.

Such abnormal native regulatory function can also be observed incirculatory diseases other than heart diseases.

Even in normal subjects, 300 to 800 mL of blood shifts to the lowerextremities and internal organs below the heart level during standing,causing decreased venous return to the heart and hypotension. Normalsubjects usually have a blood pressure regulating mechanism tocounteract this and to maintain a constant blood pressure, therebypreventing orthostatic hypotension. Subjects with various disorders anda damaged blood pressure regulating system, however, suffer fromorthostatic hypotension. For example, in patients with Shy-Dragersyndrome, a part of the nervous system involved in blood pressureregulation becomes abnormal, and quality of life is seriously impaireddue to large fluctuations in blood pressure with their body positionchange.

Artificial organs and artificial devices, such as conventionalartificial hearts and cardiac pacemakers, do not always operate inconcert with native organs, as described above, because they are notintended to be controlled by the native regulatory system. Thereforetheir performance, in terms of sensitivity to changes in the nativeorgans, is not satisfactory.

Pharmacological treatment with drugs such as coronary vasodilators,B-adrenergic blockers and anti-platelet agents, catheter-basedinterventional treatment, and coronary artery bypass surgery have beendeveloped as treatments for myocardial infarction.

However, even when taking full advantage of all of the pharmacological,interventional and surgical treatments available, progression ofpathology even to death is often inevitable.

Adrenergic agonists, such as epinephrine, levodopa and amphetamine, areused for pharmacological treatment of Shy-Drager syndrome with severeorthostatic hypertension, and excessive salt is administered forsymptomatic relief. Although symptoms can be alleviated to some extent,it is impossible to treat Shy-Drager syndrome and restore full function.

The present invention provides a cardiac pacing system, a blood pressureregulating system, and a cardiac disease treatment system that arecapable of regulating organs as if their central controllers werenormally functioning even if the central controllers themselves becomeabnormal by various causes.

SUMMARY OF THE INVENTION

A cardiac pacing system based on biological activities includes a nerveactivity sensing means which senses nerve activities of the cardiacsympathetic nerve and/or the vagal nerve, and outputs nerve activitysignals. A calculating means receives the nerve activity signals sensedby the nerve activity sensing means, analyzes and processes the nerveactivity signals to calculate pacing signals to control the heart rate,and outputs the pacing signals. A pacing means receives the pacingsignals, and stimulates the heart on the basis of the pacing signals toregulate heart rate.

A blood pressure regulating system, which uses the native regulationrule to estimate nerve activities in response to blood pressure changes,includes a blood pressure sensing means, which senses blood pressure andoutputs a blood pressure signal. A calculating means receives the bloodpressure signal sensed by the blood pressure sensing means, analyzes andprocesses the blood pressure signal to calculate a sympathetic nervestimulation signal for the regulation of blood pressure by thestimulation of sympathetic nerve innervating vascular beds, and outputsthe sympathetic nerve stimulation signal. A nerve stimulating meansreceives the sympathetic nerve stimulation signal calculated by thecalculating means, and stimulates the sympathetic nerve innervatingvascular beds on the basis of the sympathetic nerve stimulation signalto regulate blood pressure.

A system to treat cardiac diseases includes a cardiovascular activitysensing means which senses cardiovascular activity information issued bythe cardiovascular system, and outputs cardiovascular activity signals.A calculating means receives the cardiovascular activity signals sensedby the cardiovascular activity sensing means, analyzes and processes thecardiovascular activity signals to calculate nerve stimulation signals,and outputs the nerve simulation signals. A nerve stimulating meansreceives the nerve stimulation signals, and stimulates the nerve on thebasis of the nerve stimulation signals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1( a) is a schematic illustration showing the components of anative normally functioning baroreflex.

FIG. 1( b) is a schematic illustration showing how to apply the deviceused for the present invention to native abnormally functioningbaroreflex.

FIG. 2 is a block diagram depicting the outline of the device used forthe present invention.

FIG. 3( a) shows the changes in sympathetic nerve activity and heartrate with time.

FIG. 3( b) is a scatter plot showing the relationship betweensympathetic nerve activity and simultaneous heart rate, obtained by datashown in FIG. 3( a).

FIG. 3( c) is a scatter plot between the predicted heart rate obtainedfrom sympathetic nerve activity and impulse response, i.e., the requiredheart rate by organisms, on one hand, and the measured heart rate on theother.

FIG. 4 is a graph showing results obtained in Example 1.

FIG. 5 is a graph showing results obtained in Example 2.

FIG. 6 is a graph showing results obtained in Example 3.

FIG. 7 is a graph showing results obtained in Example 4.

FIG. 8( a) shows orthostatic blood pressure changes of rats withimpaired blood pressure regulation but treated with stellate ganglionstimulation in Example 6.

FIG. 8 (b) shows orthostatic blood pressure changes of normal rats inExample 6.

FIG. 8( c) shows orthostatic blood pressure changes of rats withimpaired blood pressure regulation in Example 6.

DETAILED DESCRIPTION OF THE INVENTION

The device to treat diseases used for the present invention is capableof restoring native regulatory function as if the lost or abnormalnative regulatory functions became normally functioning by substitutingthe lost or abnormal native functions with the device. As an example,the device is explained by describing an application of the invention toblood pressure regulation in detail. FIG. 1( a) is a schematicillustration showing the components of a native baroreflex or bloodpressure regulation system. Information about the changes in bloodpressure is transmitted from baroreceptors to the solitary tract nucleusin the medulla oblongata. The solitary tract nucleus then in turnchanges sympathetic nerve activity to regulate blood pressure by e.g.,vasoconstriction. FIG. 1( b) is a schematic illustration where thedevice (1) used for the present invention was applied to maintain normalblood pressure regulation even when the native vasomotor center fails toachieve normal function by various causes. Blood pressure can bemaintained in a normal way by sensing blood pressure with a bloodpressure sensing means (2), by converting the blood pressure signal intothe signal for nerve stimulation with a nerve stimulating means (4) by acalculating means (3), and by stimulating the nerve with the nervestimulating means (4) according to the calculated signals.

The device to treat diseases used for the present invention is describedin more detail in the following paragraphs with reference to thefigures. FIG. 2 is a block diagram depicting an outline of the deviceused for the present invention. The disease treatment device (1)disclosed herein includes at least a biological activity sensing means(2), a calculating means (3), and an organism stimulating means (4).

The biological activity sensing means (2) can output biosignals to thecalculating means (3) by sensing biological activity information issuedby biological activities of organisms (S). Some examples of thebiological activity sensing means (2) include, but are not limited to,electrodes and pressure sensors.

Biosignals sensed by the biological activity sensing means (2) include,but are not limited to, sympathetic nerve activities and parasympatheticnerve activities, blood flow, blood pressure, body temperature,electrocardiogram, electroenchephalogram, and various biochemicalmarkers. One can choose any necessary biosignals that are required forthe device to achieve the purpose.

The number of the biological activity sensing means (2) of the device isnot limited. Although only one biological activity sensing means (2) isshown in FIG. 2, two or more biological activity sensing means may besupplied to meet the requirements of the device. If there are multiplebiological activity sensing means in the device, they may be located atthe same site or at different sites within the organism.

The calculating means (3) can analyze and process biosignals sensed bythe biological activity sensing means (2) and transferred to thecalculating means, to calculate the signals to stimulate the organism.The calculated signals are transferred to the organism stimulation means(4).

More specifically, the biosignals sensed by the biological activitysensing means (2) are fed into amplifiers (31) in the calculating means(3) for signal amplification. These amplifiers (31) preferably includefilters (not shown) capable of eliminating unnecessary higher or lowerfrequency biosignals or power line noises. The amplified signals areconverted from analog to digital signals with the aid ofanalog-to-digital (A/D) converters (32), and then transferred toanalyzers/processors (33). The analyzers/processors (33) process data tocalculate signals to be transferred to organism stimulating means (4).

To explain how the calculating means (3) analyzes and processesbiosignals, an example of regulating heart rate is provided. FIG. 3 is agraph showing the relationship between sympathetic nerve activity andheart rate of a representative rabbit. FIG. 3( a) is a graph showingsimultaneously measured changes in cardiac sympathetic nerve activityand heart rate with time. Although, as shown in FIG. 3( a), there is atendency for the heart rate to increase with an increase in cardiacsympathetic nerve activity, the correlation between nerve activity andsimultaneous heart rate is poor (see FIG. 3( b)). Therefore, it isimpossible to regulate heart rate using sympathetic nerve activityitself.

With an impulse response function of heart rate in response tosympathetic nerve activity, however, it is possible to estimate heartrate, which is considered to follow the requirements of organisms. FIG.3( c) is a scatter plot between the heart rate estimated from impulseresponse function and measured sympathetic nerve activity on one hand,and measured heart rate on the other. As shown in this figure, measuredand estimated heart rate correlated well (correlation function 0.93).

Therefore, by analyzing and processing nerve activity signals by thecalculating means (3), the heart rate actually required by organisms canbe obtained. In the above example, one can regulate heart rate bystimulating the heart electrically according to the estimated heartrate, as if it were regulated by the normal central nervous system.

In addition to the above-described example for heart rate regulation,similar related explanations are possible for other various nativeregulations that are essential for the maintenance of biologicalfunctions, such as blood pressure regulation.

Discriminating means (not shown), judging whether biosignals coming intothe calculating means (3) arise from normal biological activities orfrom abnormal biological activities, may also optionally be provided inthe calculating means (3). To discriminate between input biosignals fromnormal biological activities and input biosignals from abnormalbiological activities, information about normal-activity biosignals arestored in memory means (not shown), and the input biosignals arecompared with the stored information. When the difference exceeds apreviously determined threshold for a given time period, the signals arejudged to be abnormal-activity signals.

When the discriminating means is provided, the calculating means doesnot output signals to the organism stimulating means for input ofnormal-activity biosignals, and the native regulatory system itselfworks. On the other hand, for abnormal-activity biosignals, the deviceworks so that the signals to stimulate the organism are prepared for theorganism stimulating means by analyzing and processing biosignals tocorrect the abnormal biological activity. In other words, for inputs ofnormal biological activities, the device needs to perform no action tomaintain normal activities. For inputs of abnormal biologicalactivities, the device outputs signals to correct abnormal biologicalactivities to normal biological activities.

When more than one biological activity sensing means are provided, theanalysis and processing described above are performed for eachrespective biological activity sensing means.

The organism stimulating means (4) receives the signals to stimulate theorganism from the calculating means (3), and stimulates the organismbased on the signals. Examples of stimulation by the organismstimulating means (4) may include, but are not limited to, electricalstimulation of nerves, myocardium, cerebrum and cerebellum, stimulationwith the use of devices for drug administration, artificial pancreas,artificial hearts, and artificial ventilators.

The following section explains the device to treat diseases used for thepresent invention in detail with reference to more specific examples.First, the cardiac pacing system, the first embodiment of the presentinvention, is described.

The basic structure of the cardiac pacing system according to the firstembodiment is the same as the device (1) shown in FIG. 2. The cardiacpacing system includes at least the biological activity (in this case,nerve activity) sensing means (2), the calculating means (3) and theorganism stimulating (in this case, cardiac pacing) means (4).

The biological activity (nerve activity) sensing means (2) senses thenerve activity of the cardiac sympathetic nerve and/or the vagal nerve,and outputs nerve activity signals.

The biological activity (nerve activity) sensing means (2) arepreferably installed in both the cardiac sympathetic nerve and the vagalnerve in order to sense both the activities of the cardiac sympatheticnerve and the vagus nerve. This is because it is known that regulationof heart rate is usually related to both the cardiac sympathetic nerveand the vagal nerve. Installing the sensing devices in both the cardiacsympathetic nerve and the vagal nerve enables heart rate to be regulatedto be less when the vagal activity is enhanced, and to be regulated tobe more when the sympathetic activity is enhanced. In other words, sincethe heart is regulated by the two nerve systems, it is difficult toregulate heart rate to an arbitrary target by only one nerve system.

Although it is preferable in this embodiment to provide two biologicalactivity (nerve activity) sensing means (2) as described above, any oneof the means may be provided depending on the purpose of the system.

The biological activity (nerve activity) sensing means (2) isexemplified by an electrode but is not limited thereto so long as it isable to sense the nerve activity and output the nerve activity signals.

The calculating means (3) receives the nerve activity signals sensed bythe nerve activity sensing means (2), analyzes and processes the nerveactivity signals, and calculates and outputs pacing signals forregulating heart rate.

The nerve activity signals sensed by the nerve activity sensing means(2) and the simultaneously measured heart rate are not correlated in aone-to-one manner. Therefore, it is necessary to calculate the pacingsignals for regulating heart rate from the nerve activity signals by thecalculating means (3).

To calculate the pacing signals for regulating heart rate from the nerveactivity signals, one can use, for example, the impulse response ofchanges in heart rate in response to changes in nerve activity.

The pacing signals derived from the calculating means (3) are fed intothe organism stimulating (pacing) means (4). The organism stimulating(pacing) means stimulates the heart based on the pacing signals toregulate heart rate.

The organism stimulating (pacing) means (4) is exemplified by a cardiacpacemaker but not limited thereto so long as it can regulate heart rateby stimulating the heart based on the pacing signals.

As described in detail above, the cardiac pacing system according to thepresent invention is based on the nerve activities of the cardiacsympathetic nerve and/or vagal nerve, but does not use the nerveactivities themselves as the pacing signals. The system instead pacesthe heart based on the pacing signals with heart rate estimated from thenerve activities. Therefore, the system is excellent in specificity,sensitivity and transient response.

Next, the blood pressure regulating system, a second embodiment of thepresent invention, is explained.

The basic structure of the blood pressure regulating system according tothe second embodiment is the same as the device (1) shown in FIG. 2. Theblood pressure regulating system includes at least the biologicalactivity (in this case, blood pressure) sensing means (2), thecalculating means (3) and the organism (in this case, nerve) stimulatingmeans (4).

The biological activity (blood pressure) sensing means (2) senses bloodpressure, and outputs the blood pressure signal. The biological activity(blood pressure) sensing means (2) is exemplified as a pressure sensorbut is not limited thereto so long as it can output the blood pressuresignal by sensing blood pressure.

Baroreceptors distributed in the carotid sinus and aortic arch senseextension of arterial walls with increases in blood pressure, and causeincreased impulse transmission to the solitary tract nucleus of themedulla oblongata. In response to this, the solitary tract nucleussuppresses sympathetic nerve activity and stimulates parasympatheticnerve activity. In contrast, when blood pressure drops, stimulation ofbaroreceptors decreases, the solitary tract nucleus is suppressed,parasympathetic nerve activity is suppressed, and sympathetic nerveactivity is stimulated. These, in turn, increase heart rate and causeperipheral vasoconstriction and blood pressure is maintained. Veins alsocontract to increase venous return to the heart.

The blood pressure regulating system can be used for patients who areunable to maintain normal blood pressure due to failures in the bloodpressure regulating system.

The calculating means (3) receives the blood pressure signals sensed bythe biological activity (blood pressure) sensing means (2), analyzes theblood pressure signals, calculates signals to stimulate the sympatheticnerve that can regulate blood pressure by stimulating the sympatheticnerve innervating vascular beds, and outputs the calculated signals tostimulate the sympathetic nerve.

Similar to heart rate regulation, the blood pressure signals sensed bythe biological activity (blood pressure) sensing means (2) and thesympathetic nerve activity signals are not correlated in a one-to-onemanner in blood pressure regulation. Therefore, it is necessary tocalculate the signals to stimulate sympathetic nerve innervatingvascular beds for blood pressure regulation from blood pressure signalsby the calculating means (2).

To calculate the signals to stimulate the sympathetic nerve innervatingvascular beds for blood pressure regulation, one can use, for example,the impulse response of changes in sympathetic nerve activity inresponse to changes in blood pressure. These may be used to calculatethe signals to stimulate the sympathetic nerve that can regulate theblood pressure.

The organism (nerve) stimulating means (4) receives the signals tostimulate the sympathetic nerve calculated by the calculating means (3),and regulates blood pressure by stimulating the sympathetic nerveinnervating vascular beds based on those signals. The sympathetic nervestimulating sites are exemplified by sympathetic ganglia, surface of thespinal cord, and preferred sites in the brain, but are not limitedthereto so long as they can stimulate the sympathetic nerve.

As described in detail above, the blood pressure regulating systemaccording to the present invention is based on blood pressure, but doesnot use blood pressure itself as the signals to stimulate thesympathetic nerve. The system instead stimulates the sympathetic nervebased on the signals to stimulate the sympathetic nerve estimated fromthe blood pressure. Therefore, the system can perform stable bloodpressure regulation as native pressure regulation.

A third embodiment of the present invention is a cardiac diseasetreating system.

The basic structure of the cardiac disease treating system is the sameas the device (1) shown in FIG. 2. The cardiac disease treating systemincludes at least the biological activity (in this case, cardiacactivity) sensing means (2), the calculating means (3) and the organism(in this case, nerve) stimulating means (4).

The cardiac disease treating system is effective for correcting thecardiac function, which has become abnormal due to any one of a numberof various diseases. For example, it is known that abnormal nativeregulation is involved in the progression of cardiac diseases, andabnormal sympathetic overactivities and vagal withdrawal have been shownwith myocardial infarction. It is possible to prevent the progression ofvarious diseases by correcting the abnormal native functional state withthe system according to the present invention.

In the cardiac disease treating system, the biological activity (cardiacactivity) sensing means (2) senses cardiac activity information issuedby native cardiac activity and outputs cardiac activity signals. Cardiacactivity information sensed by the biological activity (cardiacactivity) sensing means (2) is exemplified by heart rate andelectrocardiogram information.

The calculating means (3) receives cardiac activity signals sensed bythe biological activity (cardiac activity) sensing means (2), analyzesand processes the cardiac activity signals, calculates signals tostimulate the nerve that can regulate cardiac activities by stimulatingnerves, and outputs the signals to stimulate the nerve.

Before patients get ill, the native regulatory mechanism is normallyoperating in patients to whom the cardiac disease treating systemaccording to the present invention may be applied. Once falling ill dueto any one of a number of various cardiac diseases, however, the nativeregulatory mechanism does not help the patient recover.

In the cardiac disease treating system, the calculating means (3)includes a discriminating means (not shown) to discriminate betweencardiac activity information fed into the calculating means (3) thatarises from normal biological activities and cardiac activityinformation from abnormal biological activities. In this manner, thecalculating means does not calculate signals to stimulate nervestimulating signals and does not output the signals to stimulate thenerve to the organism (nerve) stimulating means (4) when it isdetermined that the heart is functioning normally by inputting cardiacactivity information sensed by the biological (cardiac) activity sensingmeans (2). In this situation, the organism is regulated by its nativeregulatory mechanism. When it is determined that the heart is abnormallyfunctioning by inputting cardiac activity information sensed by thebiological activity (cardiac activity) sensing means (2), on the otherhand, the calculating means calculates the nerve stimulating signals tocorrect the abnormal function of the heart, and outputs the signals tothe organism (nerve) stimulating means (4).

The signals to stimulate the nerve derived from the calculating means(3) are fed into the organism (nerve) stimulating means (4). Theorganism (nerve) stimulating means (4) stimulates the nerve based on thesignals to stimulate the nerve and to regulate cardiac activities.

The organism (nerve) stimulating means (4) is exemplified by anelectrode, but is not limited thereto so long as it is able to regulatecardiac activities by stimulating the nerve based on the signals tostimulate the nerve. Nerve stimulating sites are exemplified by thevagal nerve, the aortic depressor nerve, and preferred sites in thebrain, but are not limited thereto so long as they are able to regulatecardiac activities.

Although the present invention is explained in detail with reference tothe following examples, the present invention is not limited to theseexamples.

Example 1

The anterior descending branch of the left coronary artery in 20anesthetized rats was ligated to create rats with myocardial infarction.Mortality was periodically tabulated in this group.

In 16 other rats with myocardial infarction, heart rate was decreased bystimulating the vagal nerve (pulse width: 2 msec, pulse voltage: 2 V,pulse frequency: 2 Hz) from 2 minutes after the onset of myocardialinfarction. Mortality was also periodically tabulated in this group.

In 15 additional rats with myocardial infarction, heart rate wasdecreased by stimulating the vagal nerve (pulse width: 2 msec, pulsevoltage: 2 V, pulse frequency: 5 Hz) from 2 minutes after the onset ofmyocardial infarction. Mortality was periodically tabulated in thisgroup.

The mortality results are shown in FIG. 4.

The results in this example show that all rats with myocardialinfarction but with no treatment by vagal stimulation died within 30minutes (FIG. 4( a)). On the other hand, mortality after 60 minutes fromthe onset of the test was decreased to about 60% when the vagal nervewas stimulated with a pulse frequency of 2 Hz (FIG. 4( b)). Mortalityafter 60 minutes was further decreased to about 20% when the vagal nervewas stimulated with a pulse frequency of 5 Hz (FIG. 4( c)).

These results indicate that stimulating the vagal nerve is effective inthe treatment of myocardial infarction soon after its onset.

Example 2

Since Example 1 was performed under anesthesia, the following test wasperformed to exclude the effects of anesthesia.

Blood pressure telemeter, vagal nerve tele-stimulating device andcoronary artery cuff occluders to create myocardial infarction wereimplanted in 32 rats.

When the rats had fully recovered from surgery for one week, thedescending anterior branch of the left coronary artery was occluded withthe use of cuff occluders in 12 out of 32 rats. Mortality was tabulatedperiodically with no vagal nerve stimulation.

In another 10 out of the 32 rats, the vagal nerve was stimulated (pulsewidth: 0.2 msec, pulse current: 0.1 mA, pulse frequency: 20 Hz)immediately after the occlusion of the coronary artery with cuffoccluders for 60 minutes. Mortality was tabulated periodically withvagal nerve stimulation.

In another 10 out of the 32 rats, the vagal nerve was stimulated (pulsewidth: 0.2 msec, pulse current: 0.2 mA, pulse frequency: 20 Hz)immediately after the occlusion of the coronary artery with cuffoccluders for 60 minutes. Vagal nerve stimulation was performed withlocal anesthetic application proximal to the stimulation site to preventafferent vagal stimulation to the cerebrum (to prevent rats from beingrestless with the stimulation of 0.2 mA). Mortality was tabulatedperiodically with vagal nerve stimulation.

The mortality results are shown in FIG. 5.

As shown in FIG. 5, 66% of the rats died within 60 minutes after thecoronary occlusion with no vagal stimulation (FIG. 5 (a)). On the otherhand, mortality was limited to 40% when the heart rate was decreased by20 beats per minute by vagal stimulation of 0.1 mA (FIG. 5( b)).Furthermore, with vagal stimulation of 0.2 mA, mortality was furtherlimited to 20% (FIG. 5 (c)).

After additional observation for 2 hours, i.e. at 3 hours after theonset of the test, mortality was 83% with no vagal stimulation, 50% withvagal stimulation of 0.1 mA, and 30% with vagal stimulation of 0.2 mA,expanding the disparity between the three groups of rats.

The above results indicate that reduction of mortality immediately aftermyocardial infarction is possible by correcting the abnormal regulatoryfunction with vagal stimulation, irrespective of the presence or theabsence of anesthesia.

Example 3

The following tests were performed to investigate the long-term effects.

Myocardial infarction was created under anesthesia in the same manner asin Example 1. Surviving rats after every attempt of resuscitation(survival rate after 1 week being ˜40%) underwent another surgery 1 weekafter the first surgery. Blood pressure telemeter, vagal nervetele-stimulating device and coronary artery cuff occluders to createmyocardial infarction were implanted in these rats in the same manner asin Example 2.

After an additional 1 week, in half of the rats (13 rats), vagalstimulation was started with the stimulation condition to decrease theheart rate by 20 beats (pulse width: 0.2 msec, pulse current: 0.1 to0.13 mA, pulse frequency: 20 Hz), and the vagal nerve was stimulated for10 seconds every 1 minute. The test was continued for 5 weeks. No vagalstimulation was applied to the remaining half of the rats (13 rats). Norat deaths were observed in 5 weeks.

Changes in blood pressure and heart rate were measured throughout thetest period. The results are shown in FIG. 6. FIG. 6( a) shows theresults for the rats with no vagal stimulation, and FIG. 6( b) shows theresults for the rats with vagal stimulation.

As shown in FIG. 6, heart rate progressively decreased with vagalstimulation, but blood pressure did not change significantly with vagalstimulation.

At 5 weeks, the ventricular weight of the rats was measured. The resultsare shown in Table 1.

TABLE 1 (per 1 kg of body weight) Biventricular Left ventricular Rightventricular weight weight weight With vagal 2.71 ± 0.24 g 1.86 ± 0.12 g0.85 ± 0.27 g stimulation Without vagal 3.01 ± 0.31 g 2.03 ± 0.18 g 0.98± 0.30 g stimulation

As shown in Table 1, ventricular weight was significantly smaller inrats with vagal stimulation, indicating ventricular remodeling aftermyocardial infarction was suppressed. Since ventricular remodeling isknown to correlate with mortality in the chronic phase of myocardialinfarction, the above results indicate that vagal stimulation enablesthe correction of the abnormal regulatory mechanism, resulting in adecrease in long-term mortality.

Example 4

The following tests were performed to investigate the effect of vagalstimulation on the long-term mortality.

Myocardial infarction was created under anesthesia in the same manner asin Example 1. Surviving rats after every attempt of resuscitation(survival rate after 1 week being ˜40%) underwent another surgery 1 weekafter the first surgery. Blood pressure telemeter, vagal nervetele-stimulating device and coronary artery cuff occluders to createmyocardial infarction were implanted in these rats in the same manner asin Example 2. After an additional 1 week, in half of the rats (22 rats),vagal stimulation was started with the stimulation condition to decreaseheart rate by 20 beats (pulse width: 0.2 msec, pulse current: 0.1 to0.13 mA, pulse frequency: 20 Hz), and the vagal nerve was stimulated for10 seconds every minute for 40 days. The test was continued for 180days. No vagal stimulation was applied to the remaining half of the rats(23 rats).

As shown in FIG. 7 by accumulated survival ratio during the test, 8 outof the 23 rats died, resulting in the final accumulated survival ratioof 0.57 (FIG. 7( a)). In contrast, only 1 out of the 22 rats with vagalstimulation of 0.1 to 0.13 mA died, resulting in a final accumulatedsurvival ratio of 0.95 (FIG. 7( b)).

The above results indicate that the abnormal regulatory mechanism wascorrected by vagal stimulation, and long-term mortality after myocardialinfarction can be reduced.

Example 5

In anesthetized Japanese white rabbits, the impulse response function ofheart rate in response to cardiac sympathetic nerve activity wasobtained from measured heart rate and cardiac sympathetic nerveactivity. Since heart rate fluctuation is not large enough inanesthetized animals compared to conscious animals, heart rate wasartificially altered by randomly changing pressure imposed onbaroreceptors.

Eight Japanese white rabbits were sedated and anesthetized. Pancuroniumbromide and heparin sodium were intravenously injected to eliminatecontaminated muscular activities and to prevent blood coagulation,respectively.

Bilateral carotid arteries, aortic depressor nerves, and vagal nerveswere exposed by neck incision in rabbits. Bilateral carotid arterieswere cannulated with silicone rubber tubes connected to aservo-controlled piston pump. Carotid sinus pressure was randomlychanged by applying a band-limited white noise to the servo-pump. Toavoid the effect of other baroreflex systems such as those arising fromaortic arch baroreceptor and cardiopulmonary baroreceptor, bilateralvagal nerves and bilateral aortic depressor nerves were cut. Afterthoracotomy, the left cardiac sympathetic nerve was separated and cut.To measure cardiac sympathetic nerve activity (SNA), a pair of platinumelectrodes was attached at the proximal end. Carotid sinus pressure andaortic pressure were also measured. Atrial electrocardiogram wasmeasured by attaching electrodes to the left atrial appendage. Atrialelectrocardiogram was fed into a tachometer to measure instantaneousheart rate (HR). Measured heart rate and cardiac sympathetic nerveactivity are exemplified in FIG. 3( a).

Time series of cardiac sympathetic nerve activity and heart rate weredivided into segments. Each segment was subjected to Fourier transformto determine power of sympathetic nerve activity (S_(SNA-SNA)(f)), powerof heart rate (S_(HR-HR)(f)), and cross-power between sympathetic nerveactivity and heart rate (S_(HR-SNA)(f)), then transfer function (H(f))was calculated based on the following equation (Equation 1). Impulseresponse (h(t)) was determined by the inverse Fourier transform of thetransfer function.

$\begin{matrix}{{H(f)} = \frac{S_{{HR}\text{-}{SNA}}(f)}{S_{{SNA}\text{-}{SNA}}(f)}} & (1)\end{matrix}$

How accurately heart rate can be predicted from cardiac sympatheticnerve activity with the impulse response obtained by the above procedurewas tested.

Sympathetic nerve activity and heart rate were measured similarly to theabove described method. Heart rate was predicted from sympathetic nerveactivity using a convolution integral between the above-obtained impulseresponse and the measured sympathetic nerve activity (Equation 2).

$\begin{matrix}{{{HR}(t)} = {\sum\limits_{\tau = 1}^{N}{{h(\tau)} \cdot {{SNA}( {t - \tau} )}}}} & (2)\end{matrix}$

(where N is the length of impulse response, t is time and τ is aconvolution integral parameter, and all signals were discretized atevery 0.2 s.)

The correlation coefficient between measured and predicted heart ratewas calculated to be as high as 0.80 to 0.96 (median: 0.88), and theerror between measured and predicted heart rate was 1.4 to 6.6beats/minutes (median: 3.1 beats/minutes), which was as small as1.2±0.7% of the average heart rate.

From the above results, one can conclude that heart rate can beaccurately predicted from cardiac sympathetic nerve activity.

Example 6

The rule or the logic how the native blood pressure regulatory center(vasomotor center) determines the sympathetic nerve activity in responseto blood pressure information was obtained in 10 rats. For this,baroreceptors of animals were isolated from the rest of the circulation,and changes in blood pressure caused by the regulatory function ofvasomotor center in response to changes in pressure imposed onbaroreceptors were measured. Open-loop transfer function (H_(native)) ofbaroreflex system was determined from the relation between the input(pressure on baroreceptors) and output (blood pressure). Next, changesin blood pressure in response to changes in sympathetic nervestimulation were measured. Transfer function (H_(STM→SAP)) fromsympathetic nerve activity (STM) to blood pressure (SAP) was determinedfrom these data. Transfer function (H_(BRP→STM)) of the vasomotorcenter, which characterizes the changes in sympathetic nerve activity(STM) in response to pressure on baroreceptors (BRP), was determined asH_(native)/H_(STM→SAP).

Ten rats were anesthetized and intratracheal tubes were inserted throughthe mouth for artificial ventilation. Pancuronium bromide wasintravenously injected to eliminate contaminating muscular activities.Arterial blood gas was monitored with a blood gas measurement device. Apolyethylene tube was inserted into the right femoral vein andphysiological saline was infused to avoid dehydration. Amicromanometer-tipped catheter was inserted into the aortic arch via theright femoral artery.

Bilateral carotid sinuses were isolated from the rest of the circulationto open the baroreflex feedback loop, and vagal nerves and aorticdepressor nerves were cut. Carotid sinuses were connected to atransducer and to a servo-controlled pump system with a shortpolyethylene tube.

The left greater splanchnic nerve was separated and was cut at the levelof diaphragm. A pair of teflon-coated platinum wires was attached to thedistal end. The attached ends of platinum wires were embedded insilicone rubber. The free ends of the platinum wires were connected to aconstant voltage stimulator, controlled by a computer through a D/Aconverter.

Carotid sinus pressure was changed at random between 100 to 120 mmHgusing a servo-controlled system to determine open-loop baroreflextransfer function (H_(native)). Carotid sinus pressure and bloodpressure were measured for the determination of the transfer function.

To determine the other transfer function (H_(STM→SAP)), sympatheticnerve activity was changed at random between 0 to 10 Hz while carotidsinus pressure was maintained at 120 mmHg.

The transfer function (H_(BRP→STM)) of vasomotor center, whichcharacterizes the changes in sympathetic nerve activity (STM) inresponse to pressure on baroreceptors (BRP) was determined asH_(native)/H_(STM→SAP). Because in native animals the same pressure asblood pressure acts on baroreceptors, the required instantaneoussympathetic nerve activity (STM) to reproduce vasomotor center for givenblood pressure changes (SAP) was programmed to calculate according tothe following Equation (3).

STM(t)=∫₀ ^(∞) h(τ)·SAP(t−τ)dτ  (3)

(where h(τ) is impulse response obtained by inverse Fourier transform ofH_(BRP→STM))

Then, the impaired blood pressure regulation was mimicked by fixingpressure on the baroreceptors isolated from the rest of the circulation;thereby the rats were unable to detect the blood pressure change.Changes in blood pressure of the rats were measured with an artificialpressure sensor-tipped catheter.

To substitute native vasomotor centers, sympathetic nerve activity waspredicted by a convolution integral between blood pressure change andthe impulse response of the native vasomotor center, and stimulatedceliac ganglion, a sympathetic nerve ganglion, according to thepredicted value.

How the use of estimated sympathetic nerve activity for the stimulationof celiac ganglion enables the recovery from impaired blood pressureregulation by the improvement of hypotension was evaluated after passive90-degree head-up tilt tests.

For comparison, normal rats as well as rats with impaired blood pressureregulation also underwent 90-degree head-up tilt tests to evaluatehypotension.

The results are shown in FIG. 8. FIG. 8( a) shows the changes in bloodpressure of the rats receiving celiac ganglion stimulation, FIG. 8( b)shows the changes in blood pressure of the normal rats, and FIG. 8( c)shows the changes in blood pressure of the rats with impaired bloodpressure regulation.

According to the test results in 10 rats, blood pressure decreased by34±6 mmHg in 2 seconds after head-up tilt, and by 52±5 mmHg in 10seconds in the rats with impaired blood pressure regulation. On theother hand, blood pressure decreased by 21±5 mmHg in 2 seconds and by15±6 mmHg in 10 seconds when artificial blood pressure regulation wasapplied.

As described in detail above, in one embodiment, the heart is pacedaccording to the information from cardiac sympathetic nerve and/or vagalnerve activity, but not based on the nerve activity itself Instead, itis based on the heart rate estimated from the nerve activity. Therefore,the system is excellent in specificity, sensitivity and transientresponse.

In another embodiment, sympathetic nerve stimulating signals simulatingnative regulation are estimated from blood pressure, and the estimatedsympathetic nerve stimulating signals, but not blood pressure itself,are used for blood pressure regulation. Therefore, stable blood pressureregulation is possible in the same manner as native regulation.

In another embodiment, the heart is regulated by the native regulatorymechanism when the activity of the heart is normal. The heart isregulated to restore the normal activity when the activity of the heartis abnormal.

The present invention can provide systems to treat diseases bysubstituting native biological regulatory function. This system canregulate organs as if their central controllers were normallyfunctioning even if the central controllers themselves become abnormalby various causes.

It is to be understood that the embodiments of the invention hereindescribed are merely illustrative of the application of the principlesof the invention. Reference herein to details of the illustratedembodiments is not intended to limit the scope of the claims, whichthemselves recite those features regarded as essential to the invention.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled) 11.(canceled)
 12. (canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled)16. (canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled) 20.(canceled)
 21. (canceled)
 22. (canceled)
 23. (canceled)
 24. (canceled)25. A cardiac pacing system based on biological activities, comprising:a) at least one nerve activity sensing means which senses nerve activityof a cardiac sympathetic nerve and/or a vagal nerve, and outputs aplurality of input nerve activity signals; b) a calculating means whichreceives the input nerve activity signals, calculates a transferfunction by computing a Fourier transform of normal nerve activitysignals and a normal heart rate signal from a normal cardiovascularsystem, calculates an impulse response by computing an inverse Fouriertransform of the transfer function, calculates a plurality of pacingsignals for control of a heart rate using a convolution integral betweenthe input nerve activity signals and the impulse response, and outputsthe pacing signals; and c) a pacing means which receives the pacingsignals, and stimulates the heart based on the pacing signals such thatheart rate is regulated.
 26. The system of claim 25, wherein the pacingmeans is a cardiac pacemaker.
 27. A method of treating cardiac diseasesbased on biological activities, comprising the steps of: a) calculatinga transfer function by computing a Fourier transform of normal nerveactivity signals and a normal heart rate signal from a normalcardiovascular system and calculating at least one impulse response bycomputing an inverse Fourier transform of the transfer function; b)sensing nerve activity of a cardiac sympathetic nerve and/or a vagalnerve issued by a cardiovascular system, and outputting a plurality ofinput nerve activity signals; c) calculating a plurality of pacingsignals for control of a heart rate using a convolution integral betweenthe impulse response and the input nerve activity signals, comprisingthe substep of discriminating whether the input nerve activity signalsare caused by normal cardiovascular activities or by abnormalcardiovascular activities; and d) outputting the pacing signals forcontrol of the heart rate only if the input nerve activity signals aredetermined to be caused by abnormal cardiovascular activities.
 28. Themethod of claim 27, further comprising, after step d), the steps of: e)receiving the pacing signals output in step d); and f) stimulating thenerve based on the pacing signals output in step d).